Stress hormones are associated with inflammatory cytokines and attenuation of T-cell function in the ascites from patients with high grade serous ovarian cancer.

Autor:	Aquino-Acevedo AN; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Knochenhauer H; Department of Obstetrics and Gynecology, Division of Gynecology Oncology, School of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA., Castillo-Ocampo Y; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Ortiz-León M; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Rivera-López YA; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Morales-López C; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Cruz-Robles ME; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Hernández-Cordero ER; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA., Russell S; Department of Obstetrics and Gynecology, Division of Gynecology Oncology, School of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA., Whitaker R; Department of Obstetrics and Gynecology, Division of Gynecology Oncology, School of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA., Bonilla-Claudio M; School of Dental Medicine, Ponce Health Sciences University, Ponce, PR, USA.; Division of Cancer Biology, Ponce Research Institute, Ponce, PR, USA., Chen DT; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Dutil J; Department of Basic Sciences, Division of Biochemistry, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA.; Division of Cancer Biology, Ponce Research Institute, Ponce, PR, USA.; Division of Women's Health, Ponce Research Institute, Ponce, PR, USA., Gaillard SL; Departments of Oncology and Gynecology and Obstetrics, John Hopkins University School of Medicine, Baltimore, MD, USA.; Department of Medicine, Division of Medical Oncology, School of Medicine, Duke University, Durham, NC, USA., Yi JS; Department of Surgery, Division of Surgical Sciences, School of Medicine, Duke University, Durham, NC, USA., Previs RA; Department of Obstetrics and Gynecology, Division of Gynecology Oncology, School of Medicine, Duke Cancer Institute, Duke University, Durham, NC, USA., Armaiz-Pena GN; Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA.; Division of Cancer Biology, Ponce Research Institute, Ponce, PR, USA.; Division of Women's Health, Ponce Research Institute, Ponce, PR, USA.
Jazyk:	angličtina
Zdroj:	Brain, behavior, & immunity - health [Brain Behav Immun Health] 2022 Nov 17; Vol. 26, pp. 100558. Date of Electronic Publication: 2022 Nov 17 (Print Publication: 2022).
DOI:	10.1016/j.bbih.2022.100558
Abstrakt:	Mounting evidence suggests that chronic stress and subsequent distress can promote ovarian cancer progression. These altered psychological states have been linked to sustained release of stress hormones, activation of the β-adrenergic receptors in ovarian cancer cells, and induction of pro-tumoral signaling pathways. In addition, data suggest that chronic stress promotes an inflammatory landscape highlighted by increased infiltration of tumor-associated macrophages into the ovarian tumor microenvironment (TME). In ovarian cancer, ascites is a unique TME comprised of tumor, and immune cells, which secrete pro-tumoral cytokines and chemokines that modulate tumor-associated immunity. However, our knowledge about how stress hormones impact the ascites TME remains limited. We hypothesized that the ascites harbors measurable levels of stress hormones, and accumulation of these in the ascites generates a pro-tumorigenic, inflammatory, and immunosuppressive TME. We evaluated ascites samples from 49 patients with high grade serous ovarian cancer (HGSOC) and quantified cortisol and stress hormones metabolites, metanephrine (MN), and normetanephrine (NMN) in all samples. We also measured 38 individual cytokines in the ascites, including several pro-inflammatory cytokines, such as IL-6, which were positively correlated to MN or NMN levels of those samples. Conversely, we found cortisol levels were negatively correlated to several pro-inflammatory cytokines. As T-cells are integral to the TME and our analyses identified cytokines in the ascites known to modulate T-cell function, we characterized ascites-derived T-cells and assessed the impact of stress hormones on the T-cell phenotype. Our data show an altered CD4 + /CD8 + T-cell ratio and a heterogeneous expression of exhaustion markers in T-cells from the ascites, while ascites-derived CD8 + T-cells exposed to epinephrine had decreased co-expression CD38 and Granzyme B. To extend these findings to animal models, we subjected ovarian cancer-bearing mice to daily restraint stress, which resulted in increased tumor growth in two models. Congruent with our human analyses, we detected corticosterone, MN, and NMN in the ascites from tumor-bearing mice, and these stress hormones correlated with several inflammatory cytokines. Moreover, daily restraint stress leads to increased CD4 + PD-1 + /CD8 + PD-1 + T-cell ratio in the ovarian tumor microenvironment. Overall, these data highlight a role of stress hormones in the ascites TME as a driver of tumor-associated inflammation, T-cell suppression, and disease progression. Competing Interests: RAP has served on advisory boards for Myriad Genetics and Natera. SLG has served on advisory boards for Arcus, AstraZeneca, Elevar Therapeutics, GSK, Novartis, and Immunogen. SLG has received research funding from 10.13039/100004325AstraZeneca, Clovis, 10.13039/100004328Genentech, Iovance, Tesaro/GSK, Compugen, and Tempest. SLG holds a patent that Duke University licensed to Sermonix. No other potential conflict of interest to disclose. (© 2022 The Authors.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu